Professional Documents
Culture Documents
Introduction to Neuropharmacology
Objectives
1. explain why most mechanisms of action given the neuropharmacologic drugs are
approximations.
3. describe the various events in synaptic transmission which might be altered by drugs.
6. recognize the substances which have been proposed to act as CNS neurotransmitters.
8. describe the blood brain barrier and its implications in drug therapy.
9. describe the function of, and the disorders affecting, the various CNS neuronal
systems.
1
INTRODUCTION TO NEUROPHARMACOLOGY
Central nervous system (CNS) neurotransmission and sites of drug action. CNS drugs
act primarily by affecting the synthesis, storage, release, reuptake, or degradation of
neurotransmitters (NT) or by activating receptors. NT are synthesized from precursors
accumulated or synthesized in the neurons. The NT are stored in vesicles whose membranes
contain proteins involved in NT release (synaptobrevin and synaptotagmin). The NT are
released when an action potential-mediated calcium influx initiates interaction of
synaptobrevin and synaptotagmin with neuronal membrane-docking proteins (syntaxin and
neurexin). This leads to docking and exocytosis. Synaptic NT may activate presynaptic or
post-synaptic receptors (R1, R2, and R3). The action of NT is terminated by reuptake into the
presynaptic neuron or by enzymatic degradation.
2
Present research concentrates on long-term consequences of alteration of
synaptic transmissions.
IV. Neurotransmitters
• Acetylcholine
• Amino acids
• Biogenic amines
• Peptides
• Purines (ATP, adenosine)
• Nitric acid
• Endocanabinoids
3
TABLE 18-1. Major Neurotransmitters in the Central Nervous System*
Neurotransmitter Receptors Mechanisms of Signal Neuronal Tracts Functions
Transduction
Acetylcholine Muscarinic Basal ganglia, Excitatory (M1, M3, M5, and
M1, M3, and M5 ↑ IP3 and DAG. basal nucleus of nicotinic) or inhibitory (M2 and
M2 and M4 ↓ cAMP; ↑ gK+. Meynert to cerebral M4) NT: memory, motor
Nicotinic ↑ gCa2+, gK+, and gNa+. cortex; septal area coordination and sensory
to hippocampus processing
Amino Acids
Gamma- GABAA ↑ gC1- Ubiquitous Major inhibitory NT in CNS;
aminobutyric GABAB ↑ gCa2+ and gK+ motor coordination and neuronal
Acid (GABA) (metabotropic) excitability
Glutamate and Ionotropic Widely distributed Major excitatory NT in CNS,
aspartate AMPA and KA ↑ gK+ and gNa+ throughout CNS long-term potentiation
NMDA ↑ gCa2+, gK+, and gNa+ (memory), neuronal toxicity and
Metab. (MGluR) ↓ cAMP; ↑ IP3 and DAG apoptosis, and pain processing
Glycine Strychnine- ↑ gCl- Spinal cord; brain Major inhibitory NT in spinal
insensitive stem cord; also found in brain stem;
Strychnine- Modulate NMDA motor coordination and neuronal
sensitive Receptors excitability
Biogenic amines
Dopamine D1 and D5 ↑ cAMP Nigrostriatal, Inhibitory NT; behavioral and
D2, D3, and D4 ↓ cAMP nucleus drug reinforcement, emesis,
accumbens, hormone release, mood, motor
mesolimbic, and coordination, and olfaction.
tuberoinfundibular;
chemoreceptor
trigger zone
Histamine H1 ↑ IP3 and DAG. Hypothalamic Excitatory NT; sedation, sleep,
H2 ↑ cAMP tracts to entire CNS temperature regulation, and
H3 Unknown vasomotor function
Norepinephrine Adrenergic Locus ceruleus Excitatory (α1 and β1) or
α1 ↑ IP3 and DAG (pons) to thalamus, inhibitory (α2 and β2) NT;
α2 ↓ cAMP cerebral cortex, anxiety, cerebellar function,
β1 and β2 ↑ cAMP cerebellum, and learning, memory, mood,
spinal cord; sensory processing and sleep
midbrain to
hypothalamus
Serotonin (5- 5-HT1 ↓ cAMP; ↑ gK+ Raphe nuclei Excitary (5-HT2, 5-HT3, and 5-
hydroxy-tryptamine, 5-HT2 ↑ IP3 and DAG (Central brain HT4) or inhibitory (5-HT1) NT;
or 5-HT) 5-HT3 ↑ gK- and gNa+ stem) to forebrain appetite, emotional processing,
5-HT4 ↓ cAMP and spinal cord hallucinations, mood, pain
processing, and sleep
Peptides
Opioid peptides δ, κ, and μ ↓ cAMP and gCa2+; ↑ gK+ Widely distributed, Inhibitory NT, emotions,
especially in brain hearing, motor coordination,
stem, spinal cord, neurohormone secretion, pain
and thalamus processing, taste, and vision
Tachykinins Excitatory NT; neuromodulation
Neurokinins NK1, NK2, and NK3 ↓ gK+; ↑ IP3 and DAG Primary sensory and pain processing
Substance P NK1, NK2, and NK3 ↓ gK+; ↑ IP3 and DAG neurons; cell
bodies at all levels
Hypocretin 1 and 2 involved in sleep/wakefulness
4
*AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; cAMP = cyclic adenosine monophosphate;
CNS = central nervous system; DAG = diacylglycerol, g = conductance; IP3 = inositol triphosphate; KA =
kainate; NK = neurokinin; NMDA = N-methyl-o-aspartate; and NT = neurotransmitter
V. Neurotransmitter receptors
B. Metabotropic receptors are coupled with enzymes via G-proteins and other
intermediates.
A term used to describe diffusional barriers retarding the passage of substances from
the central circulation to nerve cells.
1. molecular weight
2. lipid solubility
3. ionization at physiological pH
• less permeable
• tight junctions
• fewer pinocytotic sites
• surrounded by pericytes and astroglial processes
• carrier mediated transport
D. Sensory processing
E. Motor processing
6
Norepinephrine in the CNS
8
• Availability of tryptophan is the main
factor regulating synthesis.
• Urinary excretion of 5-HIAA (see text)
provides a measure of 5-HT turnover.
• 5-HT neurons are concentrated in the
midline raphe nuclei in the pons and
medulla, projecting diffusely to the
cortex, limbic system, hypothalamus,
and spinal cord, similar to the
noradrenergic projections.
• Functions associated with 5-HT pathways
include :
o various behavioural responses
(e.g., hallucinatory behaviour, ‘wet-
dog shakes’)
o feeding behaviour
o control of mood and emotion
o control of sleep-wakefulness
o control of sensory pathways,
including nociception
o vomiting.
• 5-HT can exert inhibitory or excitatory
effects on individual neurons, acting
either presynaptically or postsynaptically.
• The main receptor subtypes in the CNS
are 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT3.
Associations of behavioural and
physiological functions with these
receptors have been partly worked out.
Other receptor types (5-HT4-7) also occur
in the CNS, but less is known about their
function.
9
o short interneurons in the striatum and
nucleus accumbens.
• Certain neurodegenerative diseases,
especially dementia and Parkinson’s
disease, are associated with abnormalities
in cholinergic pathways.
• Both nicotinic and muscarinic acetylcholine
receptors occur in the CNS. The former
mediate the central effects of nicotine.
Nicotinic receptors are mainly located
presynaptically; there are few examples of
transmission mediated by postsynaptic
nicotinic receptors.
• Muscarinic receptors appear to mediate the
main behavioural effects associated with
acetylcholine, namely effects on arousal,
and on learning and short-term memory
• Muscarinic antagonists (e.g., hyoscine)
cause amnesia.
• Acetylcholinesterase released from neurons
may have functional effects distinct from
cholinergic transmission.
10
Excitatory amino acids (EAAs)
12